Manipal, March 02 : Researchers at the Manipal Academy of Higher Education  an Institution of Eminence Deemed to be University, have uncovered how a deadly airborne fungus selectively attacks brain cells, offering new hope for understanding and treating fungal meningitis.

The study, conducted at the Centre for Molecular Neurosciences, Kasturba Medical College  Manipal, has revealed why Cryptococcus neoformans, a life-threatening fungal pathogen, specifically targets neurons in the brain. The findings were recently published in Frontiers in Immunology.

A Silent but Deadly Threat

Cryptococcus neoformans is an opportunistic airborne fungus that can cause fatal meningoencephalitis, particularly in individuals with weakened immune systems. While scientists have long known that the fungus releases a toxic molecule called glucuronoxylomannan  once it enters the brain, it remained unclear why certain brain cells are more vulnerable than others. The MAHE research team, led by Dr Dinesh Upadhya, used cutting-edge human brain organoids, laboratory-grown mini-brain models derived from pluripotent stem cells, to recreate a human-like brain environment for the study. “Our study shows that GXM preferentially targets neurons over other brain cells,”

 Dr Upadhya. “Brain organoids allow us to understand microbial pathogenesis in a highly human-relevant system.”

Why Neurons Are More Vulnerable

To understand the mechanism behind this selective targeting, the researchers collaborated with scientists using the Schrödinger, Inc. Materials Science Suite for advanced molecular modelling. Using atomistic simulations, the team created detailed computational models of brain cell membranes. They discovered that neurons are particularly rich in a lipid molecule called phosphatidylcholine (PC). The fungal toxin GXM shows a strong attraction to this lipid, effectively guiding it toward neurons. Once attached, GXM significantly reduced synaptophysin levels, a protein essential for neuronal communication, suggesting that the infection directly disrupts brain signalling.

“This lipid-specific interaction explains why neurons are preferentially affected, leading to meningitis,” 

said Dr. Vishukumar Aimanianda, Professor of Biochemistry at MAHE and co-investigator of the study.

Opening New Treatment Pathways

The study sets a new benchmark in using human brain organoids to investigate fungal infections. By identifying the molecular basis of the fungus's targeting of neurons, researchers believe the findings could pave the way for more targeted therapies. “Understanding these interactions at a molecular level opens new avenues for developing treatments aimed at protecting brain function,”

said Dr Kavitha Saravu, Professor of Infectious Diseases at MAHE. According to researchers, the findings not only advance knowledge in fungal pathogenesis but also demonstrate the power of combining stem-cell biology with computational molecular modelling.